The goal of this Type 2 Competitive Renewal SBIR application to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is to conduct a phase I/II clinical trial to investigate the safety and early efficacy of a novel antimicrobial living human skin substitute for the treatment of a life-threatening complication of diabetes: chronic, nonhealing skin wounds. Infected, nonhealing skin wounds contribute significantly to morbidity and mortality in individuals with diabetes mellitus and are a major reason for hospitalization of people with diabetes. In the United States alone, each year there are 1.5 million new cases of diabetes diagnosed in people aged 20 years or older. Hospital discharge data indicate that up to 20% of all diabetics hospitalized in North America within a given year will experience nonhealing skin wounds usually localized on ankles, feet, and heels. Unfortunately, the number of hospital discharges in the United States for diabetes-related amputations has risen in the last decade and as of 2006, 82,000 diabetes-induced lower extremity amputations occur each year. For the diabetic patient, amputation of one limb is associated with a poor prognosis for the contralateral limb, and a decreased rate of survival in general. An alarming 85% of diabetes-related lower extremity amputations have an infected, chronic, nonhealing skin wound as a primary causal factor. To address the critical need for innovative therapeutic approaches for treatment of chronic nonhealing skin wounds, Stratatech Corporation has used the NIKS(R) cell line to generate an antimicrobial living human skin substitute. A unique property of the NIKS(R) cells is that they are a long-lived keratinocyte progenitor and consistent source of genetically uniform, non-tumorigenic, pathogen-free human cells. Because they are readily amenable to genetic modification through the use of non-viral vectors, the NIKS(R) keratinocytes are ideal for ex vivo genetic modification approaches to create human biological skin substitutes with enhanced antimicrobial capabilities. Stratatech strategically focused on the endogenous host defense peptide human cathelicidin (hCAP-18/LL-37) because it exhibits antimicrobial activity against a broad range of microorganisms, fungi, and viruses and is a critical component of innate defenses against wound infection. PUBLIC HEALTH RELEVANCE: The goal of this project is to conduct a clinical trial to investigate the safety and early efficacy of a novel antimicrobial living human skin substitute for the treatment of a life- threatening complication of diabetes: chronic, nonhealing skin wounds. An alarming 85% of diabetes-related lower extremity amputations have an infected, chronic, nonhealing skin wound as a primary causal factor. To address the critical need for innovative therapeutic approaches for treatment of chronic nonhealing skin wounds, Stratatech Corporation has used the NIKS(R) cell line to generate an antimicrobial living human skin substitute. Stratatech strategically focused on the endogenous host defense peptide human cathelicidin (hCAP-18/LL-37) because it exhibits antimicrobial activity against a broad range of microorganisms, fungi, and viruses and is a critical component of innate defenses against wound infection.